| Function: |
Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation. |
| Tissue Specificity: |
In skeletal muscle, isoform 1 is more abundant than isoform 2. |
| Involvement in Disease: |
Noonan syndrome 5: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells.
LEOPARD syndrome 2: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.
Cardiomyopathy, dilated 1NN: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. |
| Sequence Similarities: |
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily. |
| Post-Translational Modification: |
Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and Ser-494 results in its activation. Phosphorylation at Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in its inactivation. Phosphorylation at Ser-259 induces the interaction with YWHAZ and inactivates kinase activity. Dephosphorylation of Ser-259 by the complex containing protein phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading to stimulate RAF1 activity. Phosphorylation at Ser-338 by PAK1 and PAK5 and Ser-339 by PAK1 is required for its mitochondrial localization. Phosphorylation at Ser-621 in response to growth factor treatment stabilizes the protein, possibly by preventing proteasomal degradation. Phosphorylation at Ser-289, Ser-296, Ser-301, Ser-338 and Ser-621 are somehow linked to the methylation potential of cells. Treatment of cells with HGF in the presence of the methylation inhibitor 5'-methylthioadenosine (MTA) results in increased phosphorylation at Ser-338 and Ser-621 and decreased phosphorylation at Ser-296, Ser-301 and Ser-338. Dephosphorylation at Ser-338 by PPP5C results in a activity decrease. |
| Cellular Location: |
Cytoplasm. Cell membrane. Mitochondrion. Nucleus.
Colocalizes with RGS14 and BRAF in both the cytoplasm and membranes. Phosphorylation at Ser-259 impairs its membrane accumulation. Recruited to the cell membrane by the active Ras protein. Phosphorylation at Ser-338 and Ser-339 by PAK1 is required for its mitochondrial localization. Retinoic acid-induced Ser-621 phosphorylated form of RAF1 is predominantly localized at the nucleus. |
| Database Links: |
Entrez Gene: 5894 HumanEntrez Gene: 110157 MouseEntrez Gene: 24703 RatOmim: 164760 HumanSwissProt: P04049 HumanSwissProt: Q99N57 MouseSwissProt: P11345 RatUnigene: 159130 HumanUnigene: 184163 MouseUnigene: 33262 Rat |
| Synonyms: |
c Raf AntibodyC-raf AntibodyC-Raf proto-oncogene, serine/threonine kinase AntibodyCMD1NN AntibodycRaf AntibodyCraf 1 transforming gene AntibodyCraf1 transforming gene AntibodyEC 2.7.11.1 Antibodykinase Raf1 AntibodyMurine sarcoma 3611 oncogene 1 AntibodyNS5 AntibodyOncogene MIL AntibodyOncogene RAF1 AntibodyOTTHUMP00000160218 AntibodyOTTHUMP00000207813 AntibodyOTTHUMP00000209389 AntibodyProtein kinase raf 1 AntibodyProto-oncogene c-RAF AntibodyRAF AntibodyRaf 1 AntibodyRaf 1 proto oncogene serine/threonine kinase AntibodyRaf proto oncogene serine/threonine protein kinase AntibodyRAF proto-oncogene serine/threonine-protein kinase AntibodyRAF-1 AntibodyRaf1 AntibodyRAF1_HUMAN AntibodySimilar to murine leukemia viral (V-raf-1) oncogene homolog 1 AntibodyTRANSFORMING REPLICATION-DEFECTIVE MURINE RETROVIRUS 3611-MSV Antibodyv raf 1 murine leukemia viral oncogene homolog 1 Antibodyv-raf murine sarcoma viral oncogene homolog 1 Antibodyv-raf-1 murine leukemia viral oncogene-like protein 1 Antibodyvraf1 murine leukemia viral oncogene homolog 1 Antibody |
| Information: |
Target information shown above is from the UniProt Consortium. |
